Journal
BLOOD
Volume 121, Issue 11, Pages 2064-2073Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-07-444018
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Funding
- National Cancer Institute [CA16058, CA89341, CA09338]
- P50 SPORE grant [CA140158]
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Approximately 20% to 25% of patients with acute myeloid leukemia (AML) have a constitutively activated FLT3-internal tandem duplication (FLT3-ITD), and these patients exhibit a poor prognosis. Here, we report that Axl, a receptor tyrosine kinase (RTK) overexpressed and constitutively active in human AML, targets the RTK FLT3 in FLT3-ITD+ AML. Abrogation of Axl activation by soluble Axl chimeric protein (Axl-Fc) or small interfering RNA (siRNA) diminishes constitutive FLT3 phosphorylation in FLT3-ITD+ AML. In addition, inhibition of Axl activation by Axl-Fc interferes with the physical interaction between Axl and FLT3. We found that Axl-Fc, a pharmacologic Axl inhibitor, or siRNA targeting Axl inhibits cell growth, induces cell-cycle arrest and apoptosis, and relieves a block in myeloid differentiation of FLT3-ITD+ AML in vitro. Axl-Fc also suppresses the growth of human FLT3-ITD+ AML in vivo. Collectively, our data suggest that Axl contributes to the pathogenesis of FLT3-ITD+ AML through, at least in part, positive regulation of constitutive FLT3 activation. This also suggests that Axl should be pursued as a potential target for the treatment of FLT3-ITD+ AML.
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